Molecular mechanisms underlying the beneficial effects of exercise and dietary interventions in the prevention of cardiometabolic diseases : Journal of Cardiovascular Medicine

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Molecular mechanisms underlying the beneficial effects of exercise and dietary interventions in the prevention of cardiometabolic diseases

Forte, Maurizioa; Rodolico, Danieleb; Ameri, Pietroc,d; Catalucci, Danielee,f; Chimenti, Cristinag; Crotti, Liah,i; Schirone, Leonardoj; Pingitore, Annachiarak; Torella, Danielel; Iacovone, Giulianom; Valenti, Valentinam; Schiattarella, Gabriele G.n; Perrino, Cinzian; Sciarretta, Sebastianoa,j

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Journal of Cardiovascular Medicine ():10.2459/JCM.0000000000001397, December 15, 2022. | DOI: 10.2459/JCM.0000000000001397
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Metabolic disorders, such as obesity and diabetes, are increasing worldwide and represent one of the main determinants of cardiovascular diseases. According to the WHO, the prevalence of obesity tripled between 1975 and 2016, reaching pandemic proportions and representing a major socioeconomic problem as well as a challenge for healthcare systems.1 The number of diabetic people also rapidly increased in every country, from 30 to 400 million since 1985 worldwide.2 Individuals with metabolic disorders are at high risk of developing adverse cardiovascular and cerebrovascular events, such as myocardial infarction and ischemic stroke.3,4 Although the molecular mechanisms underlying the deleterious effects of cardiovascular complications induced by metabolic disorders are not completely characterized, studies performed in preclinical models of cardiometabolic diseases and in patients indicate that insulin resistance, metabolic alterations, systemic inflammation and oxidative stress are common hallmarks, which compromise cardiac and vascular function in the presence of a metabolic stress, such as hyperglycaemia and hypercholesterolemia.2,5,6 Mitochondrial dysfunction and defects of mitochondrial dynamics and autophagy are also observed.2,5,6 Targeting these mechanisms was reported to be an efficacious strategy to reduce disease progression. Several compounds acting on specific molecular players involved in mitochondrial function, autophagy and inflammation were also characterized as the integration of traditional therapies. These compounds include systemic and mitochondria-specific antioxidants, anti-inflammatory agents and natural and synthetic activators of autophagy.7,8

Cardiometabolic diseases show a complex and multifactorial etiopathogenesis, including genetic, behavioural, socioeconomic and environmental factors.3 Epidemiological data revealed that lifestyle factors, such as scarce or absent physical activity and an unbalanced diet, are also associated with an increased risk of developing cardiometabolic diseases.3,9,10 It is well documented that a diet rich in highly processed foods, as well as an excessive consumption of sugar, affects several cardiometabolic risk factors, including low-density lipoprotein (LDL) and cholesterol levels, glucose-insulin homeostasis and metabolic pathways, thereby predisposing to adverse cardiovascular events. Conversely, diets rich in fruits and vegetables were reported to reduce the risk of cardiovascular diseases.11,12 In addition to the modification of diet composition, interventions aimed at reducing calorie intake (calorie restriction) or at reprogramming the time of feeding during the day [intermittent fasting and time-restricting feeding (TRF)] were previously found to be efficacious in reducing cardiovascular complications in the presence of obesity, diabetes and metabolic syndrome.13–15 This evidence suggests that lifestyle changes aimed at modifying unhealthy dietary habits and promoting physical activity may represent powerful interventions for primary and secondary prevention of individuals at high cardiometabolic risk.

Understanding the mechanisms underlying the beneficial effects of exercise and healthy diet is also key to developing pharmacological treatments, which hold the potential to reproduce these effects.16 In this review, we discuss the current knowledge about the molecular effects of exercise and dietary restriction in preclinical models of cardiometabolic diseases and in patients, with a particular focus on oxidative stress, inflammation, mitochondrial dysfunction and autophagy.

Overview of the molecular mechanisms involved in cardiometabolic diseases

Overt type 1 and type 2 diabetes

Diabetes may directly affect cardiac structure and function independently of the presence of other risk factors, such as hypertension and coronary heart disease, causing a clinical condition termed diabetic cardiomyopathy.17 Previous lines of evidence demonstrated that both type 1 and type 2 diabetes may directly affect multiple molecular pathways in cardiac cells, finally leading to the development of myocardial oxidative stress, inflammation, cell death, mitochondrial dysfunction and metabolic derangements.18 These alterations may lead to cardiac hypertrophy, fibrosis and heart failure, in particular heart failure with preserved ejection fraction.18 However, systolic dysfunction was also observed in diabetic patients without coronary heart disease.19,20

Oxidative stress

Reactive oxygen species (ROS) directly cause cardiac hypertrophy, fibrosis and ventricular dysfunction. ROS increase in the presence of diabetes and have a direct effect on biological macromolecules, such as proteins, lipids and DNA, causing cytotoxicity. ROS-induced DNA damage leads to the accumulation of glycolytic intermediates and the activation of protein kinase C (PKC) and advanced glycation end-product (AGE) signalling, which together contribute to cardiac dysfunction.21 ROS also target sarcomere proteins thus affecting cardiomyocyte stiffness.22,23 Hyperglycaemia induces superoxide production, which reacts with nitric oxide to form peroxynitrite, resulting in reduced nitric oxide bioavailability.21 In saphenous veins and internal mammary arteries of diabetic patients undergoing coronary artery bypass surgery, the production of superoxide was reported to be dependent on the increased activity of NADPH oxidase and PKC and on the uncoupling of endothelial nitric oxide synthase (eNOS).24 Xanthine oxidase, an enzyme generating superoxide, is also activated in the heart of diabetic mice.25 Oxidative stress in diabetic myocardium is also the result of the decreased activity of the antioxidant system. In this regard, the expression of the transcription factor NF-E2-related factor 2 (Nrf2) is reduced in the hearts of streptozotocin (STZ)-induced diabetic mice,26 whereas the overexpression of antioxidant proteins improves cardiac function in experimental diabetes.27,28 ROS activate the transcription factor nuclear factor of activated T-cells (NFAT) in STZ-induced diabetic mice, which increases the expression of genes involved in atherogenesis and enhances endothelin-1-induced vasoconstriction.29,30 NFAT activation in cardiac cells during diabetes also predisposes to cardiac hypertrophy and heart failure.31 Forkhead box protein O1 (FOXO1) activity increases in response to ROS in the heart of diabetic high-fat diet (HFD)-treated mice and in diabetic (db/db) mice, resulting in the development of cardiomyopathy, whereas FOXO1 knockout mice are protected from diabetes-induced cardiomyopathy.32–34 The downregulation of insulin signalling is associated with the development of FOXO1-induced cardiomyopathy. Increased ROS production was also found to impair circadian clock synchronization of glucose and lipid metabolism.2 The overproduction of ROS during diabetes also represents a common upstream mediator of increased inflammation and mitochondrial dysfunction. These aspects will be discussed in the following sub-paragraphs.


Myocardial inflammation is also critical for the development of diabetic cardiomyopathy. Diabetic patients show high circulating levels of inflammatory mediators, which correlate with cardiac dysfunction.35 The increase in glucose and free fatty acids during diabetes induces the secretion of cytokines, chemokines and adhesion molecules in cardiac cells as a consequence of the activation of the nuclear factor kappa-light-chain-enhancer of activated B (NF-kB).18 Among cytokines, tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) represent two important contributors to the development of cardiac dysfunction, as their inhibition reduces leucocyte infiltration and cardiac fibrosis in STZ-treated models.36,37 TNF-α and IL-6 secretion also increase as a consequence of diabetes-induced expression of the high-mobility group box 1 (HMGB1) in cardiomyocytes, macrophages and cardiac fibroblasts.38 HMGB1 inhibition in type 1 diabetic mice improves cardiac function and decreases collagen deposition.39 Hyperglycaemia also induces macrophage secretion of inflammatory mediators and the activation of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-dependent inflammasome, which lead to cardiac dysfunction in a type 2 diabetic rat model induced by HFD and low dose STZ.40 In the same model, NLRP3 inhibition was found to reduce cardiac inflammation, pyroptosis, fibrosis and to improve cardiac function.40 NLRP3 inflammasome is activated also by NF-kB in type 2 diabetic models.40

Another mechanism involved in the pro-inflammatory effects of hyperglycaemia is the increase in substrates for the enzyme O-GlcNActransferase (OGT), which activates the calcium/calmodulin-dependent protein kinase IIδ (CaMKII), thereby impairing cardiac calcium handling and causing delayed afterdepolarizations in cardiomyocytes.2

Mitochondrial dysfunction

Mitochondrial dysfunction is also a hallmark of diabetes-induced cardiovascular abnormalities. Proteomic analysis of diabetic rat hearts revealed a reduced expression of proteins of the electron transport chain.17 Oxidative stress in the heart of diabetic mice was also found to increase tyrosine nitration of mitochondrial proteins, altering their structure and function and producing dysfunctional mitochondria.41 In this regard, overexpression of ROS scavengers was reported to reduce mitochondrial dysfunction and to improve cardiac function in STZ-treated mice.42

Mitochondrial dynamics, which include the process of fission, fusion and mitophagy, are also altered in diabetic models, representing a cause of mitochondrial dysfunction. Mitochondria undergo coordinated cycles of fission and fusion. Mitochondrial fission occurs when mitochondria are irreversibly damaged, whereas mitochondrial fusion is activated in the presence of reversibly damaged mitochondria. Fission-induced fragmented mitochondria are then digested by mitophagy, the selective form of autophagy for mitochondria (as further described in the text).43 Accumulating lines of evidence also demonstrated that an imbalance between fission and fusion plays a detrimental role in the cardiovascular system.43 Generally, mitochondrial fission increases, whereas fusion decreases in diabetic cardiomyopathy and in models of insulin resistance.44,45 In the myocardium of patients with type 1 diabetes mellitus, a decreased expression of mitofusin 1, a protein involved in mitochondrial fusion, was observed and inhibition of mitochondrial fission was reported to rescue cardiac dysfunction induced by lipid overload in mice.44–46 The alteration of mitochondrial dynamics observed in diabetic models also affects mitochondrial function, compromising the activity of mitochondrial electron transport chain and ATP synthesis.2

Obesity and metabolic syndrome

The accumulation of pericardial fat during obesity contributes to increased left ventricular mass and cardiac workload, often resulting in left ventricular systolic and diastolic dysfunction.4 Obesity impairs cardiac electrophysiology, leading to contractile dysfunction and atrial fibrillation.47,48 Additional physiological effects induced by obesity include an increase in blood volume and blood pressure, as a consequence of sodium retention. The latter is caused by the activation of the sympathetic nervous system and renin-angiotensin-aldosterone system (RAAS), by hyperinsulinemia and by natriuretic peptide level downregulation.49–52


Among the molecular mechanisms underlying obesity-induced cardiomyopathy, a release of inflammatory mediators (adipokines) by adipose cells plays a major role. Adipokines contribute to the development of systemic inflammation and insulin resistance, the main mediators of cardiac dysfunction.53,54 An increase in pro-inflammatory adipokines was found to activate cardiomyocyte signalling cascades responsible for the development of left ventricular hypertrophy and systolic dysfunction.55,56 An activation of immune cells also contributes to cardiomyopathy during obesity. Macrophage-induced release of pro-inflammatory cytokines, such as TNF-α and IL-6, has a direct effect on cardiomyocytes, since it stimulates the mitogen-activated protein kinase (MAPK) and NF-κB signalling and inhibits Akt.57,58 A deregulation of these pathways was previously found to be associated with maladaptive remodelling. Macrophages also induce extracellular matrix degradation and collagen deposition by cardiac fibroblasts.57,58

The role of NLRP3 inflammasome was also reported in the development of obesity-induced atrial fibrillation. NLRP3 is activated in the atrial tissue of obese mice and patients and NLRP3 knockout mice undergoing HFD-induced obesity show a reduced atrial fibrillation occurrence.59 These results suggest that selective inhibition of the NLRP3 inflammasome may be a promising strategy to reduce the risk of atrial fibrillation in obese people, independently of body weight reduction.

Obesity and metabolic syndrome also affect vascular function, leading to the reduction of oxygen delivery to hearts and other systemic districts.60 Individuals with obesity or metabolic syndrome are characterized by coronary microvascular dysfunction.60–63 Obesity-induced low-grade inflammation leads to atherosclerosis in patients.64 In particular, pro-inflammatory adipokines modulate several key mechanisms involved in atherogenesis. Perivascular adipose tissue accumulation during obesity and metabolic syndrome impairs endothelial function, in a mechanism mediated by PKC-β activation.65 The increased activity of TNF-α during obesity also induces vascular remodelling, impairs endothelium-dependent vasodilation and leads to cell infiltration, due to increased expression of the adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1).66 In addition, obesity enhances endothelin-1-mediated vasoconstriction.67

Cardiac metabolism

During obesity, cardiac metabolism exhibits a marked preference towards fatty acid oxidation (FAO).68 The overload of substrates may lead to lipotoxicity, due to the accumulation of triglyceride products, such as ceramide and DAG, which induce cardiac dysfunction.69–71 Increased FAO and lipid accumulation also contribute to cardiac insulin resistance.72 The increase in FAO observed in diabetes can be attributed to the enhanced fatty acid supply and uptake by cardiomyocytes and to the increased transcription of fatty acid metabolic enzymes. In fact, lipid accumulation activates peroxisome proliferator-activated receptor-a (PPARa), which increases the expression of genes involved in fatty acids metabolism.71 Mice with overexpression of PPARa show cardiac hypertrophy and contractile dysfunction, whereas PPAR-deficient models display reduced myocardial FAO.72

Mitochondrial dynamics and autophagy

Mitochondrial dysfunction also contributes to obesity-induced cardiomyopathy, along with altered mitochondrial dynamics and mitophagy.73 HFD-treated mice show increased cardiac mitochondrial fission, due to the activation of dynamin related protein 1 (Drp-1), a marker of mitochondrial fission, which in turn contributes to cardiomyocyte cell death.74 Obesity also impairs cardiac autophagy, leading to cardiac dysfunction.75–77 Autophagy is an evolutionarily conserved intracellular mechanism by which cells digest and recycle senescent or damaged cytoplasmic elements, including whole organelles. In recent years, autophagy has emerged as a pivotal mechanism in mediating stress response in the cardiovascular system, by limiting damage and preserving cellular integrity.78 Autophagy is initially activated in cardiomyocytes in response to short-term feeding with HFD, whereas it is progressively inhibited by chronic feeding. Autophagy reactivation attenuates the detrimental effects of obesity in the heart. Conversely, mitophagy, a specialized form of autophagy devoted to the removal of damaged mitochondria, progressively increases in HFD-induced obesity by the activation of the ULK1/RAB9 pathway, although in an insufficient manner.79,80 A pharmacological boosting of mitophagy attenuates obesity-induced cardiac dysfunction.79,80

Exercise and cardiometabolic diseases

Preclinical studies

Although physical exercise leads to adaptive cardiac remodelling and hypertrophy, a condition that is frequent in the athlete's heart, several studies demonstrated that regular and moderate physical activity elicits cardiovascular benefits in models of cardiometabolic diseases and in patients. In the apolipoprotein E–knockout (apoE−/−) mouse strain, a relevant model for the study of obesity and metabolic syndrome, physical exercise over a period of 6 weeks was reported to reduce neointimal growth and to stabilize vascular lesions in response to carotid artery injury and thrombosis.81 In LDL–receptor–deficient (LDLR−/−) mice fed with a high cholesterol diet, regular exercise reduced the thickness of the aortic valve and improved endothelial function. The beneficial effects observed in this study are associated with reduced systemic levels of oxidative stress and ROS generation in the aortic valve.82 It has been reported that ApoE -/- mice fed with a high cholesterol diet undergoing exercise show improved endothelial function and reduced atherosclerotic plaque formation. In the same study, the authors found a reduced activity of RAC1 and NADPH oxidase, the main source of superoxide, in the vascular wall.83 In the same animal model, swimming training was found to reduce atherosclerosis and rescue nitric oxide metabolism.84 Similar results were obtained in a mouse model of type 2 diabetes, wherein exercise promoted cardiac expression of eNOS and decreased superoxide production.85 In mice treated with a HFD, running improves endothelial function and mitochondrial biogenesis, due to Nox4-mediated release of hydrogen peroxide. Indeed, the protective effects of exercise were lost in systemic Nox4 knockout mice (Nox4 –/–). This evidence suggests that Nox4 is required for exercise-induced cardiovascular adaptations.86 Overall, these studies indicate that exercise reduces cardiovascular complications of obesity and diabetes through the regulation of oxidative stress and the improvement of nitric oxide metabolism.

In the hearts of diabetic aged mice, short-term exercise was reported to increase the expression of peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha, a transcription factor that promotes mitochondrial biogenesis. In addition, exercised mice show reduced levels of pro-inflammatory cytokines and cardiac inflammation.87 Exercise rescues cardiomyopathy in diabetic rats and these effects are associated with reduced cardiac apoptosis and endoplasmic reticulum stress.88 Moderate-intensity exercise improves cardiac function in type 2 diabetic mice (db/db), by enhancing gap junction communication and by reducing levels of Drp1.89 The attenuation of mitochondrial dysfunction and damage was also observed in streptozotocin-induced diabetic rats and in mice fed with diet-induced obesity (DIO).90,91 Another mechanism underlying the reduction of ROS elicited by exercise is the increased expression of cardiac mitochondrial uncoupling protein 2 (UCP2), an inner mitochondrial membrane protein that lowers mitochondrial membrane potential, thus dissipating heat and preventing ROS accumulation.92 In db/db mice, it has been shown that the progression of diabetic heart disease is attenuated when exercise is initiated before the onset of cardiac dysfunction, due to the reduction of cardiac apoptosis, fibrosis and microvascular rarefaction. In contrast, these beneficial effects are not evident if exercise is introduced when cardiac dysfunction is already established.93 Exercise training also increases glucose utilization in the hearts of diabetic rats94 and rescues contractile dysfunction in db/db mice through the restoration of calcium release by the sarcoplasmic reticulum.95

Notably, a recent study showed that voluntary running restores cardiomyogenesis in aged mice, highlighting that exercise may have remarkable effects also on cardiomyocyte self-renewal.96

Other evidence suggests that exercise modulates cardiac autophagy. Eight weeks of exercise training rescue cardiac autophagy and autophagic flux in a model of myocardial infarction, along with the improvement of mitochondrial bioenergetics.97 In a mouse model of autophagy deficiency, termed BCL2 AAA, long-term exercise training fails to protect from high-fat diet-induced glucose intolerance, suggesting that autophagy mediates the beneficial effects of exercise in the presence of metabolic stress.98 In a recent study, 16 weeks of exercise was demonstrated to reduce atherosclerosis in Apo E –/– mice fed with a HFD and to stimulate aortic endothelial autophagy, without affecting systemic levels of triglycerides and total cholesterol.99 Further studies should test whether the protective effects of exercise in models of atherosclerosis are blunted in the presence of autophagy inhibition. The molecular effects of exercise in cardiometabolic diseases are illustrated in Fig. 1.

Fig. 1:
Molecular and cellular effects of exercise in animal models of cardiometabolic diseases and in patients. The net result of systemic and cell-specific effects of exercise is the improvement of cardiac and vascular function. NO, nitric oxide. The figure was made using tools provided by Servier Medical Arts, amongst others.

Clinical studies

Preclinical evidence about the role of physical exercise in the reduction of cardiovascular complications in cardiometabolic diseases are confirmed by human studies. Elite athletes show higher life-expectancy than the general population and also show reduced risk of cardiovascular mortality.100 Five to ten minutes per day of running, even at slow speed, reduce the risk of death and cardiovascular disease in healthy individuals.101 Similarly, physical activity was reported to reduce the risk of cardiovascular mortality in obese people and in men with type 2 diabetes.102–104 The protective effects of exercise on vascular function were demonstrated in different trials. Exercise improves endothelial function in overweight and obese adults.105,106 For instance, 8th weeks of combined aerobic and resistance exercise training ameliorates endothelial function in diabetic patients.107 Another study shows that 6 months of aerobic exercise fail to rescue microvascular dysfunction in diabetic people,108 but they are able to reduce the thickness of carotid intima-media in patients with type 2 diabetes mellitus, along with the improvement of glycaemic control, blood pressure level and BMI.109 Endurance exercise also improves endothelial function in patients with coronary artery disease (CAD), increases nitric oxide bioavailability and enhances large artery elasticity in overweight and obese older adults.110–112

Other studies investigated the effects of exercise on cardiac function in humans. The CARDIO-FIT trial showed that physical activity reduces the risk of atrial fibrillation in overweight and obese individuals with symptomatic atrial fibrillation.113 In obese patients with heart failure with preserved ejection fraction (HFPEF), aerobic exercise training increases peak oxygen consumption and reduces systemic inflammation and left ventricular mass.114 A reduction of markers of inflammation, such as C-reactive protein (CRP) and IL-6, is also observed in diabetic patients.115 Physical activity also induces weight loss in obese individuals and reduces insulin resistance.116 In this regard, weight loss following 8 weeks of exercise correlates with the improvement of subclinical cardiovascular dysfunction in obese individuals.117 Other effects on metabolism include the control of glycaemic levels and insulin sensitivity.118 Overall, this evidence suggests that physical activity exerts beneficial effects in cardiac and vascular cells by acting on nitric oxide metabolism, oxidative stress and inflammation, which may be in part dependent on the reduction of adipose tissue and insulin resistance. The modulation of mitochondrial dynamics in response to exercise was also observed in patients. Exercise promotes mitochondrial fusion and decreases mitochondrial fission in human muscle skeletal biopsies and also increases markers of general autophagy.119,120 An upregulation of autophagy was also observed in peripheral blood mononuclear cells (PBMCs) isolated from individuals undergoing short-term exercise.121 In a recent study, exercise upregulates the expression of autophagic markers in the adipose tissue of obese and diabetic patients.122 However, in another study, autophagy markers were not modulated in skeletal muscle biopsies of type 2 diabetic patients undergoing exercise.123,124 Further studies should correlate the levels of circulating markers of autophagy with vascular and cardiac function in obese and diabetic individuals undergoing exercise, in addition to muscle cells and PBMCs.

Dietary restriction and cardiometabolic disease

Preclinical studies

Dietary restriction represents another promising intervention for the prevention of cardiovascular complications induced by obesity, diabetes and metabolic syndrome. Calorie restriction, defined as the reduction of calorie intake (30–40% of reduction) without malnutrition, was reported to elicit health-promoting effects in chronic diseases, such as neurodegenerative disease and cancer.125 CR exerts important antiageing effects. In this regard, calorie restriction increases lifespan and reduces cardiovascular ageing in different organisms.126 Calorie restriction also modulates cellular metabolism. The latter includes changes in the lipid profile, such as the reduction of triglycerides and LDL cholesterol, as well as the reduction of glucose and insulin levels and the improvement of insulin sensitivity. Other evidence points to the effects of calorie restriction on the endocrine system, wherein it reduces the secretion of insulin-like growth factor-binding protein 1 (IGFBP1) and angiotensin I.127 Calorie restriction also reduces inflammation, mitochondrial dysfunction and oxidative stress, whereas it activates autophagy in the cardiovascular system.8 Additional molecular effects of calorie restriction are mediated by the modulation of nutrient-sensing pathways. Calorie restriction activates 5’ adenosine monophosphate-activated protein kinase (AMPK), histone (de)acetylase sirtuin1 (SIRT1), and protein kinase B (PKB, also known as Akt) and inhibits the insulin/IGF1-like signalling pathway (IIS) and the mammalian target of rapamyicin complex (mTORC)1.8 These signalling cascades are known modulators of autophagy. The physiological consequences of the metabolic and molecular effects of calorie restriction are the improvement of endothelial function and heart rate variability, as well as the reduction of low-intima-media thickness and blood pressure levels.8

The effects of calorie restriction were studied in models of cardiometabolic diseases. The incidence of cardiovascular diseases and diabetes was lower in rhesus monkeys undergoing calorie restriction.128,129 In db/db mice, calorie restriction was found to reduce cardiac fibrosis and leukocytes infiltration and markers of toll-like receptors (TLRs) activation and to rescue serum levels of free fatty acids.130 In the same animal model, the protective effects of calorie restriction were associated with the restoration of SIRT1 and PGC1-alpha activity.131 Mild (20% food intake reduction) and short-term (2 weeks) calorie restriction was reported to reduce cardiac issues in obese rats and this effect was independent of the modulation of the cardiac metabolic profile.132 Another study demonstrated that calorie restriction for 4 months rescues cardiac dysfunction in younger obese mice, but fails to exert the same effects in older animals. The beneficial effects observed in younger obese mice were attributable to the decrease in oxidative stress and to the improvement of NOS activity.133 Other reports demonstrated that calorie restriction is able to rescue cardiac dysfunction in diabetic and obese mice and rats and this effect is associated with the improvement of autophagy.134,135 Combined calorie restriction and exercise were found to improve cardiac function in obese insulin-resistant rats and rescue mitochondrial dysfunction and apoptosis in the heart. Remarkably, the cardiac protective effects of calorie restriction as well as exercise were more pronounced if compared with the single intervention.136 Calorie restriction also exerts vascular protective effects. Calorie restriction reduces atherosclerotic lesions and levels of oxidative stress in the aorta of Apo E –/– mice, whereas it rescues endothelial function and autophagic flux in the aorta of db/db mice.137,138 The molecular effects of calorie restriction in cardiometabolic diseases are summarized in Fig. 2.

Fig. 2:
Molecular and cellular effects of calorie restriction in animal models of cardiometabolic diseases and in human. The net result of systemic and cell-specific effects of calorie restriction is the improvement of cardiac and vascular function. NO, nitric oxide. The figure was made using tools provided by Servier Medical Arts, amongst others.

Intermittent fasting, characterized by the alternation of fasting and re-feeding cycles, also exerts beneficial effects in models of obesity and diabetes.139 Six months of intermittent fasting reduces cardiovascular risk factors in rats.140 TRF [for animals and time-restricted eating (TRE) for patients] represents a form of intermittent fasting that maintains a daily cycle of feeding and fasting with a circadian rhythm (Fig. 3). Irregular eating times have been reported to increase cardiovascular risk factors.141,142 Accordingly, disruption of circadian genes affects glucose and lipid homeostasis, insulin resistance and other hallmarks of metabolic disease.143 The metabolic effects of intermittent fasting and TRF are represented by a shift from fat to ketone metabolism and modulation of cellular adaptive responses, such as autophagy.144–146

Fig. 3:
Schematic representation of dietary restriction interventions. In the figure are schematized common forms of Intermittent fasting, such as alternate-day feeding and time-restricted feeding. The figure was made using tools provided by Servier Medical Arts, amongst others.

Previous studies demonstrated that TRF prevents DIO and metabolic disorders in mice.147–149 From a molecular point of view, TRF affects the mTOR, AMPK and CREB pathways in the liver150 and also restores the expression of genes regulating circadian rhythm.151 Studies performed in Drosophila revealed that TRF exerts cardiovascular protective effects. In this model, TRF was found to reduce cardiac ageing and high-fat diet-induced cardiac dysfunction. The cardiac protective effects of TRF were mediated by the increased expression of genes encoding for the TCP-1 Ring Complex (TRiC) chaperonin and by the reduced expression of genes encoding for the mitochondrial electron transport chain complexes.148 Finally, TRF during the light-phase was reported to rescue the circadian rhythm of blood pressure levels through the inhibition of sympathetic activity in obese mice.152 Further studies should investigate cardiac and vascular molecular effects of intermittent fasting and TFR in mouse and rat models of cardiometabolic diseases.

Clinical studies

Dietary restriction protocols were also tested in human clinical trials. Long-term calorie restriction was reported to improve diastolic function in healthy individuals and to reduce markers of inflammation, fibrosis and blood pressure levels.153,154 Six-month calorie restriction induces weight loss and reduces cardiovascular risk in healthy nonobese individuals.155 In line with this evidence, long-term CR (6 years) was reported to reduce the risk of atherosclerosis, highlighted by the reduction of carotid artery intima-media thickness (IMT).156 Calorie restriction improves cardiovascular function in type 2 diabetic and obese patients with CAD, along with the reduction of body weight.157 The reduction of risk factors for the development of CAD was also observed in nonobese subjects undergoing calorie restriction.158 The CALERIE study demonstrated that CR reduces blood pressure levels and lipid profile in healthy, nonobese individuals159 and it also improves biomarkers of longevity, metabolic adaptation and oxidative stress in overweight individuals.160,161 The protective effects of calorie restriction are also those mediated by the reduction of autonomic function, which in turn improves heart rate variability.162 In patients with type 2 diabetes, calorie restriction was found to reduce sympathetic tone and RAAS activity.163 Calorie restriction also inhibits the IGF-1/insulin pathway and improves levels of autophagic markers and mediators of quality control mechanisms in skeletal muscle.164,165 It would be interesting to evaluate in the future whether these pathways are also modulated in the heart and vessels of individuals with cardiometabolic diseases.

The protective effects of intermittent fasting and TRE were also observed in patients. Intermittent fasting reduces cardiovascular risk factors in young overweight women.166 An intermittent fasting protocol consisting of calorie consumption limited to 8 h during day-time was reported to reduce cardiovascular risk factors in resistance-trained men.167 Early TRE in the morning also improves insulin sensitivity, and reduces blood pressure levels and oxidative stress in men with prediabetes.168 Consistently with this, 10-h TRE for 12 weeks reduces blood pressure and LDL cholesterol levels in patients with metabolic syndrome.169 Alternate-day fasting, another form of intermittent fasting, also decreases cardiovascular risk factors in obese adults.170

Conclusion and future perspectives

The evidence gathered here suggests that lifestyle interventions, such as exercise and dietary restriction or a combination of both reduce cardiovascular complications of obesity and diabetes, both in preclinical models and in patients. In summary, exercise and dietary restriction rescue cell metabolism, with a net result of weight loss and also reduce systemic inflammation and oxidative stress. Exercise and dietary restriction also target specific molecular mechanisms, such as autophagy and mitochondrial dynamics. However, some studies failed to dissect whether the protective effects exerted by exercise or calorie restriction in the cardiovascular systems are mediated by systemic or cell-specific effects. Mechanistic studies should clarify this aspect, by evaluating, for example, the effects of calorie restriction and exercise in loss-of-function models of autophagy or circadian genes.

The clinical application of exercise and dietary modifications to patients with cardiometabolic diseases also presents some limitations. People may be reluctant to adopt a correct lifestyle or to perform regular physical activity, showing low compliance to specific diet or training recommendations. To overcome this problem, several compounds, both natural and synthetic, called calorie restriction mimetics (CRM), mimic the physiological and molecular effects of calorie restriction and could be used in place of calorie restriction and exercise.8 Multiple lines of evidence demonstrated that different CRM are able to improve cardiac function and reduce ageing in preclinical models of cardiovascular diseases.8 At a molecular level, CRM were reported to reduce the acetylation of intracellular proteins leading to nutrient depletion and autophagy activation.171 Spermidine, a polyamine present in different foods, such as soybeans and nuts, is a promising CRM that was found to extend lifespan in mice and to reduce cardiac complications induced by ageing in an autophagy/mitophagy-dependent manner.172 Remarkably, epidemiological data revealed that dietary intake of spermidine is associated with low incidence of cardiovascular diseases and increased longevity in individuals.172,173 Other CRM, such as rapamycin, resveratrol, curcumin and epigallocatechin-3-gallate were also found to improve cardiac function in mouse models of type 2 diabetes and obesity.174–178 It will be interesting to compare the cardiovascular effects of CRM and dietary restriction interventions in clinical trials. Moreover, CRM are generally well tolerated, in some cases already FDA-approved, and for these reasons, they may be introduced as adjuvants of traditional therapy or as preventive tools for reducing cardiometabolic risk factors.


The authors thank the Italian Society of Cardiology for the continuous support to the activities of the study group, including the preparation of this manuscript.

Conflicts of interest

There are no conflicts of interest.


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calorie restriction; cardiometabolic diseases; diabetes; exercise; obesity

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